Because of the skin's accessibility, autoimmune diseases of the epidermis, such as vitiligo, are amenable to study using minimally invasive techniques. In addition, potential therapeutic agents can be tested locally. The long-term goal of this project is to develop a novel fusion protein useful for treating autoimmune disorders of the epidermis. Activated T cells, which cause autoimmune destruction, express an immunosuppressive receptor on their surface called Programmed Death-1 (PD-1). PD-Ligand 1 (PD-L1) binds to the PD-1 receptor to generate signals that inactivate T cells. This pathway is important in many physiologic systems, including maintenance of chronic viral infections, tumor immune evasion, and normal tolerance in the prevention of autoimmunity. We have developed a potentially therapeutic molecule consisting of the extracellular domain of PD-L1 that is fused to a non-pathogenic antibody against desmoglein 3 (Dsg3). Because Dsg3 is constitutively expressed on mouse and human keratinocytes, intradermal or intravenous injection of this fusion protein targets the epidermis. By targeting delivery of the immunosuppressive protein PD-L1 to the epidermis, we will determine if we can suppress T cell activation in the epidermis and halt progression of epidermal inflammation or prevent its initial triggering. To test this hypothesis, we will first determine if the fusion protein suppresses a human allogeneic T cell response to cultured primary keratinocytes in vitro. Then, we will test whether local or systemic administration of this fusion protein can arrest onset or progression of disease in a mouse model of vitiligo. Finally, we will confirm that the fusion protein targets human keratinocytes in human skin xenografts on mice. This research has the potential to impact clinical care for patients with autoimmune disorders involving the epidermis and other epithelia. The project will provide preliminary results for an NIH K-award or new investigator RO1 application.